[unreadable] We hypothesize that the formation of dendritic varicosities.in response to substance P (SubP) is a novel and as yet unappreciated morphological mechanism for the long-term regulation of neuronal excitability. The occurrence of dendritic varicosities (DVs) is well-documented and there is a sound theoretical basis for their ability to alter neuronal excitability, yet their functional significance remains unknown. We have preliminary evidence for their physiological relevance, and occurrence in brainstem neurons implicated in the regulation of nociception and reward mechanisms. The aim of this CEBRA application is to test the hypothesis that the formation of DVs is a morphological mechanism by which the excitability of neurons can be regulated longterm. Whole-cell voltage-clamp recordings from rostral ventromedial medullary (RVM) neurons in brainstem slices will be used to establish the functional relevance of DVs with respect to synaptic transmission. The first Specific Aim will use conventional and confocal light microscopic analyses to determine (1) the timecourse of DV formation in NK1-ir RVM GABA neurons, (2) the ability of microtubule stabilizing drugs, such as taxol, to prevent the formation of DVs, and (3) the ability of NK1 receptor antagonists to block the formation of DVs. Blockade of synaptic transmission by TTX will be used to determine whether DVs induced by SubP are mediated by a direct effect rather than the release of other transmitters. The results of these studies will form the anatomical basis for understanding the effect of DVs on the conduction of synaptic potentials in NK1-ir RVM GABA neurons. The second Specific Aim will use whole-cell voltage clamp recordings to (1) characterize how the formation of DVs alters the passive membrane properties of RVM neurons including cytosolic resistance and (2) determine whether the formation of DVs influences the conduction of synaptic potentials -in RVM neurons. These latter studies will determine whether the formation of DVs is associated with changes in (a) the resting membrane currents, (b) the conduction of synaptic currents, and (c) stimulus evoked input-output curves of RVM neurons. Collectively, the results of these studies will establish the formation of DVs as a means to regulate the conduction of synaptic potentials and excitability of brainstem neurons. The significance of this application lies in its characterization of a potentially important and novel mechanism that may control neuronal excitability. [unreadable] [unreadable] [unreadable] [unreadable]